Inhibition of homodimerization of Toll-like receptor 4 by curcumin

Biochem Pharmacol. 2006 Jun 28;72(1):62-9. doi: 10.1016/j.bcp.2006.03.022. Epub 2006 Apr 1.

Abstract

Toll-like receptors play a key role in sensing microbial components and inducing innate immune responses. Ligand-induced dimerization of TLR4 is required for the activation of downstream signaling pathways. Thus, the receptor dimerization may be one of the first lines of regulation in activating TLR-mediated signaling pathways and induction of subsequent immune responses. LPS induces the activation of NF-kappaB and IRF3 through MyD88- or TRIF-dependent pathways. Curcumin, a polyphenol found in the plant Curcuma longa, has been shown to suppress the activation of NF-kappaB induced by various pro-inflammatory stimuli by inhibiting IKKbeta kinase activity in MyD88-dependent pathway. Curcumin also inhibited LPS-induced IRF3 activation. These results imply that curcumin inhibits both MyD88- and TRIF-dependent pathways in LPS-induced TLR4 signaling. However, in TRIF-dependent pathway, curcumin did not inhibit IRF3 activation induced by overexpression of TRIF in 293T cells. These results suggest that TLR4 receptor complex is the molecular target of curcumin in addition to IKKbeta. Here, we report biochemical evidence that phytochemicals (curcumin and sesquiterpene lactone) inhibit both ligand-induced and ligand-independent dimerization of TLR4. Furthermore, these results demonstrate that small molecules with non-microbial origin can directly inhibit TLRs-mediated signaling pathways at the receptor level. These results imply that the activation of TLRs and subsequent immune/inflammatory responses induced by endogenous molecules or chronic infection can be modulated by certain dietary phytochemicals we consume daily.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • Cell Line / drug effects
  • Curcumin / pharmacology*
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Dimerization
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation / drug effects
  • Genes, Reporter
  • Humans
  • Immunoblotting
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Interleukin-1 Receptor-Associated Kinases
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Ligands
  • Mice
  • Myeloid Differentiation Factor 88
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Sesquiterpenes / chemistry
  • Sesquiterpenes / pharmacology
  • Signal Transduction / drug effects
  • Toll-Like Receptor 4 / metabolism*
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Enzyme Inhibitors
  • Interferon Regulatory Factor-3
  • Intracellular Signaling Peptides and Proteins
  • Irf3 protein, mouse
  • Ligands
  • MYD88 protein, human
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Sesquiterpenes
  • TICAM-1 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Cyclooxygenase 2
  • Interleukin-1 Receptor-Associated Kinases
  • Protein-Serine-Threonine Kinases
  • Curcumin